The inhibitory activity associated with myelin has been proposed to be a major obstacle for successful axon regeneration in the adult central nervous system (CMS). Recent studies from our laboratory as well as others have shown that Nogo, myelin associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp) collectively account for the majority of this myelin-associated inhibition. All three molecules bind to a common GPI-linked Nogo-66 receptor (NgR) with high affinity, with signal transduction across the axonal membrane mediated by two transmembrane co-receptors, including a TNF receptor family member p75 and a newly-identified transmembrane protein Lingo-1. However, it remains unknown how these two co-receptors relay the specific signals across the axonal membrane. In addition, p75 expression has only been shown in subpopulations of mature neurons in the adult CMS, raising the possibility of the existence of other functional equivalent(s) of p75. Our preliminary results suggest that TROY, a newly identified member of the TNF receptor family that is selectively expressed in the adult nervous system, might act as a p75-equivalent co-receptor. Like p75, it can form a physical and functional receptor complex with NgR and Lingo-1 to mediate cellular responses to myelin inhibitors. Also, a truncated TROY lacking its intracellular domain can efficiently block neuronal responses to myelin inhibitors. Thus, we hypothesize that together with Lingo-1, both p75 and TROY may function interchangeably as co-receptors for transducing the inhibitory signals across the axonal membrane. The objective of this study is to investigate how these two signal transducers (p75/TROY and Lingo-1) transduce the signals across axonal membrane in regulating the process of axon regeneration. In the first aim, we will examine the functional relationship between p75 and TROY. The second aim will investigate the downstream signaling mechanisms mediated by p75, TROY and perhaps other functionally similar molecules. The involvement of Lingo-1 in this receptor complex will be addressed in the third aim.